Indole Ring System Research Articles

Biomimetically Inspired Synthesis of Exotine A.

Exotine A, which comprises an unusual coumarin-cyclohepta[ b]indole ring system, has been synthesized for the first time in a one-pot process from known starting materials. The key step features a biomimetically inspired combination of three components to deliver exotine A and 11'- epi-exotine A in 43% yield and 17:1 diastereomeric ratio. Some mechanistic aspects of this reaction are discussed.

Synthesis, Characterization and Evaluation of Anti-inflammatory and Analgesic Activity of Some Novel Quinoline Based Thiazolidinone Heterocycles

In this paper we report the synthesis of some quinoline based thiazolidinone derivatives (13–22) in a three-step process. Condensation of 2-hydrazinylquinoline 2 with different aromatic aldehydes gave the corresponding Schiff bases 3-10 which in turn were reacted with thioglycolic acid to furnish the corresponding thiazolidinone derivatives 13-20. Reaction of compound 2 with isatin or methyl isatin gave 1-sustituted-3-(2-(quinolin-2-yl)hydrazono)indolin-2-ones 11 and 12, which were converted to 1-substituted 3'-(quinolin-2-ylamino)spiro[indoline-3,2'-thiazolidine]-2,4'-dione 21 and 22 by cyclocondensation with thioglycolic acid. All newly synthesized compounds have been characterized by means of elemental analyses, IR, 1H NMR and MS. Furthermore, all new thiazolidinone derivatives were evaluated for their anti-inflammatory and analgesic activity. The Study results revealed that the highest anti-inflammatory potency was gained by 6 derivatives according to the following order 22 > 17 >13 > 14 > 21 > 15, showing a good edema inhibition compared to the reference drug indomethacin. Compound 22 carrying indole ring system inhibited the edema volume significantly at the 1st h post administration, and the activity was enhanced up to the 4th h giving a promising edema volume inhibition compared to that produced by indomethacin. The longest duration of analgesic action up to 90 min post compounds administration was obtained by the compounds 13, 17 and 22, they exhibited a potent analgesia compared to that obtained by aspirin.

Alkyne Insertion into P–C(sp2) Bonds as a Route to Fused Phospholes: Transition-Metal-Like Reactivity at Phosphorus

While alkyne insertion into metal–carbon(sp2) bonds is common in transition metal chemistry, direct alkyne insertions into E–C(sp2) bonds are very rare in main group chemistry. Herein, we report a direct alkyne insertion reaction into the P–C(aryl) bonds of tungsten-coordinated phenyl-aryl phosphenium ions, which lead to phenyl-vinyl phosphenium ions. The insertion reaction is followed by electrophilic substitution of the phosphenium ion onto the aryl group, leading to a net annulation reaction and formation of arene and heteroarene-fused phospholes. The regioselectivity of the products and computational chemistry have been used to elucidate the insertion-electrophilic substitution mechanism. This methodology has been used to synthesize known benzophosphole and phospholo[3,2-b]thiophene and new phospholo[3,2-b]pyrrole, phospholo[2,3-b]pyrrole, and phospholo[2,3-b]indole ring systems.

Crystal structure and optical spectroscopic analyses of (E)-3-(1H-indol-2-yl)-1-(4-nitro-phen-yl)prop-2-en-1-one hemihydrate.

The asymmetric unit of the title compound, 2C17H12N2O3·H2O comprises two mol-ecules of (E)-3-(1H-indol-2-yl)-1-(4-nitro-phen-yl)prop-2-en-1-one and a water mol-ecule. The main mol-ecule adopts an s-cis configuration with respect to the C=O and C=C bonds. The dihedral angle between the indole ring system and the nitro-substituted benzene ring is 37.64 (16)°. In the crystal, mol-ecules are linked by O--H⋯O and N-H⋯O hydrogen bonds, forming chains along [010]. In addition, weak C-H⋯O, C-H⋯π and π-π inter-actions further link the structure into a three-dimensional network. The optimized structure was generated theoretically via a density functional theory (DFT) approach at the B3LYP/6-311 G++(d,p) basis level and the HOMO-LUMO behaviour was elucidated to determine the energy gap. The obtained values of 2.70 eV (experimental) and 2.80 eV (DFT) are desirable for optoelectronic applications. The inter-molecular inter-actions were qu-anti-fied and analysed using Hirshfeld surface analysis.

Study of the anti(myco)bacterial and antitumor activities of prolinate and N-amidocarbothiolprolinate derivatives based on fused tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione, bearing an indole ring

A series of prolinate and N-amidocarbothiolprolinate derivatives based on a fused pyrrole-3,4-dione core, bearing indole ring systems, are prepared from the corresponding amino acid and an aldehyde via thermal 1,3-dipolar cycloaddition of azomethine ylides and condensation with benzoylisothiocyanate. Products are fully characterized by NMR, FT-IR, MS, and an X-ray crystal structure. The prepared compounds are screened for their antibacterial activity against a range of Gram-positive and Gram-negative bacteria and their antimycobacterial activity against M. tuberculosis H37Rv strain. In addition, two selected target compounds are evaluated for cytotoxicity, apoptosis, and anti-inflammatory effects on MCF-7 (breast carcinoma) cell lines. The incorporation of indole ring and –C(O)NHC(S)– moiety resulted to be beneficial since the biological point of view.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The Food and Drug Administration has approved drugs (e.g., rivastigmine, donepezil, galantamine, and memantine) that at best provide marginal benefits, thus emphasizing the urgent need to explore other molecular entities as future drug candidates for AD. Looking at the wide pharmaceutical applications of heterocyclic compounds and particularly those containing benzofuran and indole ring systems, these molecular frameworks have drawn special attention from medicinal chemists for further evaluation in numerous diseases. This article focuses on the history and recent advances of benzofuran- and indole-based compounds as inhibitors of butyrylcholinesterase, acetylcholinesterase, γ-secretase, β-secretase, tau misfolding, and β-amyloid aggregation.

A new approach to the pyrrolo[3,4-b]indole ring system

A new approach to the pyrrolo[3,4-b]indole ring system

4-(1H-Indol-3-yl)-2,6-bis(pyrazin-2-yl)pyridine

In the title compound, C21H14N6, the pyridine ring and two pyrazine rings are nearly coplanar [dihedral angles = 2.03 (7) and 1.60 (7)°], while the dihedral angle between the indole ring system and the pyridine ring is 29.04 (6)°. In the crystal, molecules are linked by N—H...N hydrogen bonds, which generate [-110] chains. The packing is consolidated by C—H...N hydrogen bonds and aromatic π–π stacking, generating a three-dimensional network.

Crystal structures and antioxidant capacity of (E)-5-benzyloxy-2-{[(4-chlorophenyl)imino]methyl}phenol and (E)-5-benzyloxy-2-({[2-(1H-indol-3-yl)ethyl]iminiumyl}methyl)phenolate

The title Schiff base compounds, C20H16ClNO2 (I) and C24H22N2O2 (II), were synthesized via the condensation reaction of 2-amino-4-chloro-phenol for (I), and 2-(2,3-di-hydro-1H-indol-3-yl)ethan-1-amine for (II), with 4-benz-yloxy-2-hy-droxy-benzaldehyde. In both compounds, the configuration about the C=N imine bond is E. Neither mol-ecule is planar. In (I), the central benzene ring makes dihedral angles of 49.91 (12) and 53.52 (11)° with the outer phenyl and chloro-phenyl rings, respectively. In (II), the central benzene ring makes dihedral angles of 89.59 (9) and 72.27 (7)°, respectively, with the outer phenyl ring and the mean plane of the indole ring system (r.m.s. deviation = 0.011 Å). In both compounds there is an intra-molecular hydrogen bond forming an S(6) ring motif; an O-H⋯O hydrogen bond in (I), but a charge-assisted N+-H⋯O- hydrogen bond in (II). In the crystal of (I), mol-ecules are linked by C-H⋯π inter-actions, forming slabs parallel to plane (001). In the crystal of (II), mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers. The dimers are linked by C-H⋯O hydrogen bonds, C-H⋯π inter-actions and a weak N-H⋯π inter-action, forming columns propagating along the a-axis direction. The anti-oxidant capacity of the synthesized compounds was determined by cupric reducing anti-oxidant capacity (CUPRAC) for compound (I) and by 2,2-picrylhydrazyl hydrate (DPPH) for compound (II).

Supramolecular Complexation of Biologically Important Thioflavin‐T with p‐Sulfonatocalix[4]arene

AbstractThe inclusion of thioflavin T (ThT) with p‐sulfonatocalix[4]arene (p‐SC4) is briefly discussed in solution as well as solid state. The restricted rotation of C−C single bond between indole and benzene ring system is the reason for emission property of ThT. The encapsulation of ThT using a flexible charged host molecule exploit the correlation between the C−C single bond rotation and emission enhancement. The binding of ThT with p‐SC4 in solution state is studied using absorption, emission, electrochemical, 1H NMR and rotating frame nuclear overhauser effect spectroscopy (ROESY) techniques. A stable water insoluble supramolecular complex is synthesized from water soluble ThT and p‐SC4. The structural features of the prepared solid complex is established from infrared (FT‐IR), powder X‐ray diffraction (XRD), Mass, 1H NMR and nuclear overhauser effect spectroscopy (NOESY) analyses.

Correlation of vapor phase infrared spectra and regioisomeric structure in synthetic cannabinoids

The twelve 1-n-pentyl-2-, 3-, 4-, 5-, 6- and 7-(1- and 2-naphthoyl)-indoles each have the same substituents attached to the indole ring, identical elemental composition (C24H23NO) yielding identical nominal and accurate masses. These twelve isomers cover all possible positions of carbonyl bridge substitution for both indole (positons 2–7) and naphthalene rings (positions 1 and 2). Regioisomeric compounds can represent significant challenges for mass based analytical methods however, infrared spectroscopy is a powerful tool for the identification of positional isomers in organic compounds. The vapor phase infrared spectra of these twelve uniquely similar compounds were evaluated in GC-IR experiments. These spectra show the bridge position on the indole ring is a dominating influence over the carbonyl absorption frequency observed for these compounds. Substitution on the pyrrole moiety of the indole ring yields the lowest CO frequency values for position 2 and 3 giving a narrow range from 1656 to 1654cm−1. Carbonyl absorption frequencies are higher when the naphthoyl group is attached to the benzene portion of the indole ring yielding absorption values from 1674 to 1671cm−1.The aliphatic stretching bands in the 2900cm−1 region yield a consistent triplet pattern because the N-alkyl substituent tail group remains unchanged for all twelve regioisomers. The asymmetric CH2 stretch is the most intense of these three bands. Changes in positional bonding for both the indole and naphthalene ring systems results in unique patterns within the 700 wavenumber out-of-plane region and these absorption bands are different for all 12 regioisomers.

Crystal structure of diethyl 3,3'-[(4-nitro-phen-yl)methyl-ene]bis-(1H-indole-2-carboxyl-ate).

In the title compound, C29H25N3O6, the mean planes of the two indole ring systems (r.m.s. deviations = 0.0115 and 0.0082 Å) are approximately perpendic-ular to one another, making a dihedral angle of 89.7 (5)°; the benzene ring is twisted with respect to the two indole ring systems by 52.6 (4) and 88.2 (3)°. In the crystal, pairs of N-H⋯O hydrogen bonds link the mol-ecules into the inversion dimers, which are further linked into supra-molecular chains along the b-axis direction. Weak C-H⋯O hydrogen bonds and C-H⋯π inter-actions are also observed in the crystal.

One-pot synthesis of novel 3,10-dihydro-2H-1,3-oxazepino[7,6-b]indoles via 1,4-dipolar cycloaddition reaction

3,10-Dihydro-2H-1,3-oxazepino[7,6-b]indoles are synthesized via a convenient one-pot three-component 1,4-dipolar cycloaddition reaction, involving 3-alkyl(aryl)imidazo[1,5-a]pyridines, dimethyl acetylenedicarboxylate (DMAD) and N-alkylisatins. Structures of the newly synthesized heterocycles are evidenced from spectral data and further confirmed by single crystal X-ray diffraction. A plausible reaction mechanism is advanced, whereby the intermediate 1,4-dipole, generated in situ from imidazo[1,5-a]pyridine and DMAD, initially adds to the keto group of N-alkylisatins to form the corresponding 1,3-oxazin-spiro-oxindole cycloadduct. The latter undergoes subsequent unprecedented skeletal rearrangement through a cascade of bond breaking and bond making processes, eventually leading to ring enlargement, furnishing the tricyclic oxazepino[7,6-b]indole ring system as the end product.

Crystal structure of diethyl 3,3'-[(2,4-di-chloro-phen-yl)methyl-idene]bis-(1H-indole-2-carboxyl-ate).

In the title compound, C29H24Cl2N2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.1249 and 0.0075 Å) are approximately perpendic-ular to one another, with a dihedral angle of 80.9 (5)° between them. The benzene ring is inclined to the mean planes of the two indole ring systems by 76.1 (3) and 78.3 (4)°. Weak intra-molecular C-H⋯π inter-actions affect the mol-ecular conformation. In the crystal, pairs of N-H⋯O hydrogen bonds link the mol-ecules into inversion dimers which are further linked into supra-molecular chains by N-H⋯O hydrogen bonds and short Cl-Cl contacts.

Crystal structure of diethyl 3,3'-[(2-fluoro-phen-yl)methyl-idene]bis-(1H-indole-2-carboxyl-ate).

In the title compound, C29H25FN2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.1392 and 0.0115 Å) are approximately perpendicular to one another, subtending a dihedral angle of 86.0 (5)°; the benzene ring is twisted with respect to the mean planes of the two indole ring systems by 83.3 (2) and 88.1 (4)°, respectively. In the crystal, pairs of N-H⋯O hydrogen bonds link the mol-ecules into centrosymmetric dimers, which are further linked by N-H⋯O hydrogen bonds into supra-molecular chains propagating along the [101] direction.

Methyl (1-benzamido-2-methoxy-2-oxoethyl)tryptophanate

The title molecule, C22H23N3O2, is U-shaped, with a dihedral angle of 80.76 (9)° between the indole ring system and the phenyl ring. In the crystal, N—H...O hydrogen bonds combine with N—H...π and C—H...π interactions to generate a three-dimensional structure.

Crystal structures of 1-benzene-sulfon-yl-2-methyl-3-(4-nitro-benzoyl)-2,3-di-hydro-1H-indole and 1-benzene-sulfon-yl-2-methyl-3-[(thio-phen-2-yl)carbon-yl]-2,3-di-hydro-1H-indole.

In the title indole derivatives, C22H16N2O5S, (I) and C20H15NO3S2, (II), the sulfonyl-bound phenyl rings are almost orthogonal to the indole ring system, subtending dihedral angles of 88.33 (10) and 87.58 (16)°, respectively. In both compounds, the sulfonyl S atom has a distorted tetra-hedral geometry [O-S-O = 119.98 (9) and N-S-C = 104.01 (8)° for compound (I) and O-S-O = 120.08 (18) and N-S-C = 104.91 (14)° for compound (II)] and the sum of the bond angles at N indicates sp2 hybridization. The mol-ecules of both (I) and (II) feature intra-molecular C-H⋯O hydrogen bonds that generate S(6) ring motifs with the sulfone O atom. In the crystals, mol-ecules of (I) are linked by C-H-O hydrogen bonds, forming R44(18) ring motifs while mol-ecules of (II) are linked by C-H-O and C-H-S hydrogen bonds, forming R22(12) ring motifs. Compound (II) was refined as an inversion twin.

(R*)-1-Benzyl-3-(2-hydroxyphenyl)indoline-2-one

The title compound, C21H17NO2, crystallizes with two independent molecules (AandB) in the asymmetric unit. The indoline ring system is almost planar in both molecules (r.m.s. deviations = 0.020 and 0.024 Å for moleculesAandB, respectively). The benzyl and phenol rings are inclined to the indole ring system by 80.39 (12) and 68.39 (12)° in moleculeA, and by 79.90 (13) and 74.88 (10)° in moleculeB. The aryl rings are inclined to one another by 33.30 (14) and 30.62 (14)° in moleculesAandB, respectively. In the crystal,Amolecules are linked by pairs of O—H...O hydrogen bonds, forming inversion dimers. The same situation is observed for theBmolecules and both sets of inversion dimers encloseR22(14) ring motifs. These dimers stack along thea-axis direction and are linked by offset π–π interactions [intercentroid distance = 3.6802 (13) Å] involvingAandBindole ring systems, forming layers parallel to theabplane.

Crystal structure and DFT study of (E)-N-[2-(1H-indol-3-yl)eth-yl]-1-(anthracen-9-yl)methanimine.

The title compound, C25H20N2, (I), was synthesized from the condensation reaction of anthracene-9-carbaldehyde and tryptamine in dry ethanol. The indole ring system (r.m.s. deviation = 0.016 Å) makes a dihedral angle of 63.56 (8)° with the anthracene ring (r.m.s. deviation = 0.023 Å). There is a short intra-molecular C-H⋯N inter-action present, and a C-H⋯π inter-action involving the two ring systems. In the crystal, the indole H atom forms an inter-molecular N-H⋯π inter-action, linking mol-ecules to form chains along the b-axis direction. There are also C-H⋯π inter-actions present, involving the central and terminal rings of the anthracene unit, linking the chains to form an overall two-dimensional layered structure, with the layers parallel to the bc plane. The density functional theory (DFT) optimized structure, at the B3LYP/6-311 G(d,p) level, is compared with the experimentally determined mol-ecular structure in the solid state.

(2Z)-2-(5-Fluoro-1-methyl-2-oxoindolin-3-ylidene)-N-(3-fluorophenyl)hydrazine-1-carbothioamide

In the title compound, C16H12F2N4OS, the whole molecule is essentially planar (r.m.s deviation = 0.003 Å), with only the H atoms of the methyl group lying out of the molecular plane. A planar indole fused-ring system (r.m.s deviation = 0.004 Å) is linked through a hydrazine–carbothioamide bridge to a fluorobenzene ring, with the indole ring system and inclined to the fluorobenzene ring by 4.26 (14)°. The planarity of the molecule is strengthened by three intramolecular N—H...N, N—H...O and C—H...S hydrogen bonds that generateS(5),S(6) andS(6) ring motifs, respectively. In the crystal, π–π stacking interactions combine with C—H...·F hydrogen bonds to link the molecules into layers parallel to the (10-1) plane.